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PubMed1986

The direct and amplifying effects of serotonin are increased with age in the isolated perfused kidney of Wistar and spontaneously hypertensive rats.

Isolated kidneys of Wistar rats and spontaneously hypertensive rats (SHR) were perfused with Tyrode's solution. In 2- and 6-month old SHR, the maximal increase in perfusion pressure caused by norepinephrine was higher than in 2- and 6-month old Wistar rats, but the sensitivity, as judged from the dose of the agonist required to reach 50% of the maximal response was the same. Both the maximal response and the sensitivity to serotonin were significantly augmented in 6-month old SHR and Wistar rats when compared to the young animals. This hypersensitivity was more pronounced in SHR than in Wistar rats. Infusion of serotonin potentiated the vasoconstriction induced by a bolus of norepinephrine. This amplification, due to activation of S2-serotonergic receptors, was more pronounced in the old animals. No amplification occurred when norepinephrine was infused instead of serotonin. Tachyphylaxis to the amplifying effect of serotonin was observed and was less pronounced in kidneys from old than from young animals. The amplifying effect of serotonin was inhibited by ketanserin at concentrations which did not, or only moderately, inhibit the response to norepinephrine.

Aging↗
PubMed1986

Electrophysiological actions of somatostatin (SRIF) in hippocampus: an in vitro study.

The electrophysiological actions of somatostatin (somatotropin release inhibiting factor; SRIF) were investigated in the in vitro hippocampal slice preparation. Intracellular recordings were obtained from pyramidal neurons in area CA1 in slices of hippocampus from guinea pigs and rabbits. Somatostatin, applied via micropressure ejection to CA1 pyramidal-cell somata, was primarily excitatory. The effects, however, were quite variable, with nearly all cells displaying pronounced tachyphylaxis. A majority of cells was depolarized by SRIF, but hyperpolarizations or biphasic depolarization/hyperpolarization responses were also recorded. Only minimal conductance changes were associated with the SRIF-induced voltage changes. Depletion of SRIF, by injection of the intact animal with cysteamine several hours before preparing slices, resulted in no obvious abnormalities in hippocampal slice electrophysiology. Our results obtained with application of exogenous SRIF are consistent with the concept that SRIF acts as an excitatory neurotransmitter/neuromodulator in hippocampus. However, our attempts to demonstrate endogenous SRIF action have thus far been unsuccessful.

Animals↗
PubMed1985

On the nature of the contractile motor responses of the rat stomach elicited by serotonin or substance P in vitro.

SP or 5-HT elicited contractile motor responses from strip preparations of the rat antrum and pylorus, effects which were efficiently antagonized by blockade directed against each substance (SP-receptors: tachyphylaxis or a SP analogue; 5-HT2 receptors: ketanserin). Indirect effects of SP or 5-HT, i.e. causing the release of other spasmogens such as histamine (from mast cells) and prostaglandins, were ruled out in separate experiments using pyrilamine or indomethacin. When the contractile effects of SP or 5-HT motor responses were studied after TTX no inhibition was demonstrated indicating that the effects were mediated via muscle receptors. Both SP- and 5-HT-responses were partially antagonized by blockade of muscarinic or nicotinic receptors, even in the presence of TTX, in favour of interaction at the receptor level of the smooth muscle membrane. One exception was the SP-induced pyloric contraction, which was partially atropine-sensitive but resistant to hexamethonium. Interestingly, blockade of 5-HT2 receptors (ketanserin) reduced the contractile response to SP. These observations indicate an interaction between SP and 5-HT receptors at the smooth muscle membrane. However, SP and 5-HT added together did no facilitate the response. Therefore, the interaction of ketanserin with the SP response may rather be sterical than due to binding to a common receptor site. These findings may be of importance, since SP and 5-HT have recently been shown to coexist in gut neurons.

Animals↗
PubMed1995

Involvement of substance P as a mediator in capsaicin-induced mouse ear oedema.

We examined the involvement of substance P (SP) in mouse ear oedema induced by topical application of capsaicin (250 micrograms/ear). Reapplication of capsaicin at 4 h, 24 h, and 48 h after initial treatment did not induce a second oedema response. Oedema induced after the second application was significantly (p < 0.01 or p < 0.001) suppressed for up to 30 days but was observed when capsaicin was applied 40 days after initial treatment. Topical pretreatment of ears with capsaicin at 4 h, 24 h and 48 h before i.v. injection of SP (5 micrograms/kg) did not cause a significant inhibition of plasma extravasation in ear skin. NK1 receptor antagonists such as RP 67580 (ED50:0.19 mg/kg, i.v.), spantide II (ED50:0.33 mg/kg, i.v.), and GR 82334 (ED50:0.26 mg/kg, i.v.), inhibited capsaicin-induced ear oedema, whereas SR 48968 (2.0 mg/kg, i.v.), a NK2 receptor antagonist, had no effect. Furthermore, RP 67580 (0.5 kg/mg, i.v.) inhibited the oedema response induced by reapplication of capsaicin at 50 days after initial treatment. These results indicate that tachyphylaxis of capsaicin-induced oedema is reversible and suggest that this response may be due mainly to a reduction of SP in sensory neurones but not to any loss of responsiveness of NK1 receptors. We also conclude that SP and NK1 receptors are involved predominantly in the development of capsaicin-induced mouse ear oedema.

Animals↗
PubMed1990

Prolonged treatment with oral and inhaled tulobuterol does not induce airways tachyphlaxis.

Beta 2-agonists have been shown to induce beta 2-adrenoceptor downregulation in vivo and in vitro. Whether this has any functional relevance remains unclear. Tulobuterol is a new synthetic beta 2-agonist with potent and prolonged bronchodilator activity when given by oral and inhaled routes. The effect of tulobuterol aerosol (400 micrograms q.i.d.) and tulobuterol tablets (2 mg b.i.d.) was studied in patients with chronic asthma and reversible airways obstruction in two separate trials. Tulobuterol produced significant bronchodilatation after the first and final dose over a 6-h period and the effects were comparable. The bronchodilator activity of tulobuterol given by inhalation and oral routes was not attenuated after 6 months of continuous treatment. There was significant improvement in symptom score and lung function measurements. Side effects, predominantly tremors, were observed at the start of treatment with tablet formulation but the incidence and severity of tremors decreased after 6 months. The changes in BP and pulse rate were not clinically significant. These results confirm the potent bronchodilator activity of tulobuterol and the lack of tachyphylaxis after prolonged treatment.

Administration, Inhalation↗
PubMed2004

[Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 patients].

BACKGROUND AND OBJECTIVES: The perception of pruritus is modified by endogenous and exogenous opioids via central opiate receptors and can be suppressed with opioid receptor antagonists. The aim of this investigation was to describe the efficacy and safety of naltrexone, an orally active opiate antagonist, in the treatment of severe, otherwise intractable pruritus of varying origins. PATIENTS: A total of 133 patients with pruritus caused by inflammatory skin diseases (asteatotic dermatitis, atopic dermatitis, prurigo, and psoriasis vulgaris), liver- and renal diseases, cutaneous lymphoma, as well as with pruritus of unknown origin were treated with naltrexone (Nemexin) 50 to 150 mg daily. RESULTS: A therapeutic response was achieved in 86 of the 133 (64.6%) patients. Naltrexone was most effective in prurigo nodularis, cutaneous lymphoma and pruritus of unknown origin. Tachyphylaxis occurred in 13% of the patients, but appeared late, and could be counterbalanced by raising the dosage. Adverse drug effects were restricted to the first two weeks of treatment and included mainly neurological (dizziness, headache, fatigue) and gastrointestinal (nausea, vomiting, diarrhea) symptoms. CONCLUSIONS: The oral opiate antagonists may well be an effective, well-tolerated therapy for intractable pruritus in many diseases.

Administration, Oral↗
PubMed2006

[Ultrastructural changes in human nasal mucosa in rhinitis medicamentosa].

BACKGROUND: Long-term abuse of decongestive nasal drops causes rhinitis medicamentosa due to cytotoxic and ciliary-toxic effects. Nasal obstruction is caused by rebound swelling when the decongestive effect has disappeared. The patient starts using nasal drops more frequently as a result of tachyphylaxis. PATIENTS AND METHODS: Tissue samples from human inferior turbinates from 22 patients who had overused decongestive nose drops were taken during nasal surgery and preserved in phosphate-buffered paraformaldehyde or glutaraldehyde. Ultrathin sections were cut. The samples were dehydrated and embedded in Araldit. The findings were photo-documented using a light- and transmission electron microscope. Biopsies from ten patients without chronic inflammation of the nasal mucosa were used as controls. RESULTS: The electron microscopic investigations revealed epithelium showing severe damage corresponding to regions with hyperplastic and metaplastic changes. Loss of ciliated cells was observed. Under a thick basal membrane, ultrastructural changes to the endothelial lining, such as openings and rupture of the basal lamina, were detected. Prominent endothelial cells were conspicuous. CONCLUSIONS: Rhinitis medicamentosa is a drug-induced injury to human nasal mucosa associated with the prolonged abuse of topical nasal decongestants. Loss and destruction of ciliated epithelial cells are the morphological correlation to the disturbance of mucociliary clearance. Endothelial cells of capillaries, in particular, revealed ultrastructural changes indicative of increased permeability with consecutive interstitial edema.

Administration, Intranasal↗
PubMed1983

Pharmacodynamics of ritodrine in pregnant women during preterm labor.

We evaluated the relationship of ritodrine concentration to several maternal variables and to fetal heart rate in 17 women who received the drug for inhibition of preterm labor. Ritodrine was measured by high-performance liquid chromatography with electrochemical detection. Ritodrine increased maternal and fetal heart rate and decreased serum potassium in a dose-related manner, but wide variability was noted between patients and within individual patients. Tachyphylaxis of the maternal heart rate response to continuing treatment with ritodrine was seen in at least seven women. Maternal blood pressure, serum glucose concentration, and frequency of uterine contractions were changed by ritodrine treatment, but the changes in these variables were not closely correlated to the concentration of ritodrine (r less than or equal to 0.30 in all cases). The maximal infusion rate and the concentration of ritodrine in maternal serum after 4 hours of treatment were significantly (p less than 0.001) correlated with the frequency of uterine contractions prior to treatment. Successful inhibition of labor was achieved with serum concentrations of 15 to 31 ng/ml in 10 of 17 women; in six of the other seven women, labor could not be inhibited in spite of serum concentrations of 90 to 146 ng/ml. Side effects, such as hypotension, vomiting, chest discomfort, and shortness of breath, were most commonly observed when the infusion rate and concentration of ritodrine were increasing.

Blood Pressure↗
PubMed1980

Spinal noradrenergic terminal system mediates antinociception.

Intrathecal administration of norepinephrine (NE) into the lumbar subarachnoid space of rats and cats implanted with chronic spinal catheters produced a strong, dose-dependent, behaviorally defined analgesia. The effect appeared mediated by an alpha-receptor inasmuch as phenylephrine, but not isoproterenol produced the intrathecal effect. Moreover, the antinociceptive effect of NE was antagonized by the prior systemic or intrathecal administration of phentolamine (an alpha-blocker), but was unaffected by pretreatment with propranolol (a beta-blocker). The effect of intrathecal NE was significantly potentiated by prior administration of Lilly 51641 (a monoamine oxidase inhibitor) and protriptyline (a re-uptake inhibitor), and was not antagonized by the intrathecal administration of a non-specific vasodilator, papaverine. The antinociceptive effect of intrathecal NE showed tachyphylaxis following repeated injections. No cross-tolerance between intrathecal NE and morphine was observed, suggesting that the spinal action of morphine is not mediated by spinal noradrenergic terminals. Importantly, naloxone had no effect on the intrathecal NE effect. The present data provide further evidence for the modulatory role of a spinal noradrenergic system on the spinal processing of nociceptive transmission.

Animals↗
PubMed1984

Action of intrathecal capsaicin and its structural analogues on the content and release of spinal substance P: selectivity of action and relationship to analgesia.

Intrathecal injections of capsaicin (CAP) and 4 other homovanillic acid (HMV) derivatives related to the structure of CAP were carried out. Capsaicin, 1-nonenoylvanillylamide (NVA), HMV-dodecylamide (DCA) (but not HMV-cyclohexylamide (CHA) or HMV-hexadecylamide (HDC] reduced the spinal content of substance P (SP), as measured by radioimmunoassay (RIA), and increased the tail-flick latency. Similar injection of kainic acid and piperine reduced levels of SP but failed to affect the tail-flick latency. None of the agents used affected spinal levels of cholecystokinin (CCK) or vasoactive intestinal peptide (VIP) as measured by RIA. In experiments using in vivo superfusion of the rat spinal cord, CAP, DCA and NVA were found to stimulate release of SP. Capsaicin had no effect on the levels of CCK or VIP immunoreactivity in the spinal superfusate. A tachyphylaxis to the effect of CAP and DCA on spinal SP release was demonstrated. Pretreatment with either agent blocked the releasing effect of the second. Pretreatment with an inactive analogue (HDC) had no effect on the subsequent activity of CAP. Kainic acid and piperine did not induce release of SP from the spinal cord. The relative selectivity of spinally administered capsaicinoids with regard to their effects on the content and release of peptides known to be contained in primary afferents and the presence of a similar structure-activity relationship for depletion and release of SP, desensitization and antinociception suggest the presence of a specific receptor site associated with a specific population of primary afferents through which pain information may pass. Whether SP is an 'afferent pain transmitter' is not clear, but at the least, it appears to serve as a marker for a population of afferents acted upon by spinally administered capsaicinoids.

Animals↗
PubMed1975

Comparative vasodilator effects of nitroglycerin, pentaerythritol trinitrate and biometabolites, and other organic nitrates.

Previous studies in man have shown pentaerythritol (PE) trinitrate, given either sublingually or orally, produces a prolonged hypotensive effect. The coronary vasodilator and systemic vasodepressor activities of PE trinitrate and its metabolites, PE dinitrate, PE mononitrate and PE, were evaluated in dogs to determine whether the metabolites were active and contributory. Coronary vasodilator activity was estimated with a flow transducer placed on the left anterior descending artery, and reduction of arterial pressure was determined directly via the femoral artery. Quantitative comparisons were made from dose-response curves established for nitroglycerin (ng), PE nitrates, and other common organic nitrates after intrajugular administration. Increase of coronary blood flow and reduction of arterial pressure were proportionally related, and the proportionality was the same for all drugs. Relative to NG, the potency of PE trinitrate was about 20 percent, erythrityl tetranitrate 12 percent, and isosorbide dinitrate 3.5 percent. The ratios of vasodilator activity of PE trinitrate and its metabolities were: PE trinitrate 100; PE dinitrate 1.5; PE mononitrate 0.5; and PE O. Tachyphylaxis was observed after close-order injections of NG or PE trinitrate. In addition, there was cross tolerance between NG and PE trinitrate and also between PE trinitrate and its less active metabolites.

Animals↗
PubMed1975

The effects of arachidonic acid, indomethacin and SC-19220 on guinea-pig tracheal muscle tone.

The effects on guinea-pig tracheal muscle of a prostaglandin synthesis inhibitor, indomethacin, antagonist, SC-19220, and precursor, arachidonic acid have been studied in order to investigate the possible role of prostaglandins in the maintenance of respiratory smooth muscle tone. Indomethacin reduced the resting tone of the muscle, and increasing concentrations reduced the response to arachidonic acid without affecting the response to acetylcholine. Prostaglandins E2 and F2alpha caused contractions of indomethacin-relaxed muxcle, and tachyphylaxis was induced by repeated exposure of the muscle to these agonists, but not to arachidonic acid. The prostaglandin antagonist, SC-19220 relaxed the muscle and abolished its response to a standard dose of prostaglandin E2. Increasing concentrations of SC-19220 reduced the responses to both arachidonic acid and large doses of prostaglandin E2. The responses of tracheal muscle to arachidonic acid are concluded to be partly due to prostaglandin synthesis, supporting the hypothesis that this process maintanins tracheal muscle tone.

Acetylcholine↗
PubMed1975

Differences between the effects of dopamine and apomorphine on rat aortic strips.

Dopamine and apomorphine have been compared with regard to contraction and relaxation of aortic strips prepared from rats of different ages. Both dopamine and apomorphine contracted aortic strips from older (9-12 weeks) rats to greater maximal tension than preparations from younger (3--5 weeks) animals. Contraction in response to both agonists could be blocked by the alpha-blocker, Dibenamine. In contrast to dopamine contraction by apomorphine was associated with the development of tachyphylaxis. Both apomorphine and dopamine relaxed the aorta after alpha blockade, however, the relaxation produced by these drugs differed in two major aspects. First, dopamine-induced relaxation was greatest in aortic strips from young rats compared to older rats whereas relaxation with apomorphine was not age dependent. Second, dopamine-induced relaxation was abolished by propranolol but not haloperidol whereas apomorphine relaxation was only blocked by haloperidol. These data establish that the aortic relaxation caused by dopamine is most likely a beta-adrenergically mediated response whereas that produced by apomorphine is not. Moreover, only dopamine was able to increase the concentration of rat aortic cyclic AMP. Should these data be applicable to other vascular beds or species, it is possible that the vascular effects of dopamine will be influenced by age and drugs which impinge on cyclic nucleotide disposition.

Age Factors↗
PubMed1975

The action of bombesin on gastric secretion of the chicken.

The natural tetradecapeptide bombesin at a threshold dose of 3--5 ng/kg/min i.v. stimulates gastric secretion in the chicken with either an acute or a chronic proventriculus fistula; this effect is blocked by atropine. The occurrence of tachyphylaxis in the acute, but not in the chronic preparation, and the inhibition of the response by proventriculus acidification, in the presence of an intact sensitivity to caerulein -- a directly stimulating agent -- support the hypothesis of an indirect mechanism of action of bombesin, namely the release of endogenous gastrin, as well as of the existence of gastrin also in the chicken.

Animals↗
PubMed1977

The effects of arachidonic acid in isolated atria of guinea pigs.

The effects of free and albumin-bound arachidonic acid, which is the precursor of the prostaglandins E2 and F2alpha, were studied on the spontaneous rate, contractile force and myocardial fatty acid metabolism in isolated, spontaneously beating atria of guinea pigs. Both free and albumin-bound arachidonic acid (10(-6)-10(-3) M) produced a dose-dependent positive chronotropic and a modest inotropic action. Tachyphylaxis to the positive chronotropic action of arachidonic acid developed in the course of repeated applications. Beta-Adrenoceptor blockade (pincolol) and pretreatment with reserpine or prostaglandin-synthetase inhibitors (indomethacin, fenoprofen, aspirin, 5,8,11,14-eicosatetraynoic acid) failed to affect the chronotropic activity of arachidonic acid significantly. The action of arachidonic acid was independent of the decarboxylation of the fatty acid. Linoleic and oleic acids did not show any positive chronotropic activity. The data are interpreted as suggesting that changes induced by arachidonic acid might be partly due to peroxides formed from arachidonic acid.

Animals↗
PubMed1988

Neuromedin U octapeptide alters ion transport in porcine jejunum.

The gut neuropeptide, neuromedin U octapeptide (NMU-8) produced transient elevations in short-circuit current (EC50 = 0.7 nmol/l) after its contraluminal administration to sheets of porcine distal jejunal mucosa in vitro. Mucosal responses to NMU-8 were unaffected by 1 mumol/l atropine or hexamethonium, but were abolished by tetrodotoxin (0.1 mumol/l), dependent upon extracellular Cl, and underwent tachyphylaxis upon repeated peptide application. NMU-8 did not affect contractility of isolated jejunal longitudinal muscle. Thus, NMU-8 appears to selectively modify intestinal ion transport through interactions with non-cholinergic enteric neurons.

Animals↗
PubMed1990

Effects of piperine on the motility of the isolated guinea-pig ileum: comparison with capsaicin.

Piperine (1 microM), a congener of capsaicin, produced an initial contraction blocked the capsaicin-sensitive contractile response to mesenteric nerve stimulation and inhibited the twitch response induced by field stimulation in the isolated guinea-pig ileum. These three effects of piperine (1 microM) were rapidly desensitized and significantly antagonized by ruthenium red (0.5-1 microM), an inorganic dye known to antagonize the effects of capsaicin. The contractile effect of piperine was abolished by application of tetrodotoxin plus desensitization with substance P or by extrinsic denervation. The inhibitory effect of piperine (1 microM) on the twitch response was antagonized by desensitization with calcitonin gene-related peptide (CGRP). Moreover, cross-tachyphylaxis between piperine and capsaicin was observed, suggesting that a similar mechanism may be involved in the effects of these agents. The contractile effects induced by piperine (10 microM) and the subsequent inhibitory effects on the twitch response were not desensitized and largely persisted after extrinsic denervation. The contractile effects of piperine (10 microM) were not strongly inhibited by tetrodotoxin plus desensitization with substance P. It was concluded that the lower concentration of piperine caused contraction and inhibited the twitch responses by releasing substance P and CGRP, respectively, from sensory nerves, and blocked the response to mesenteric nerve stimulation by a mechanism similar to that of capsaicin. At higher concentrations, piperine had non-specific direct actions on the smooth muscle.

Alkaloids↗
PubMed1992

Effect of resiniferatoxin on the isolated rabbit iris sphincter muscle: comparison with capsaicin and bradykinin.

The effect of resiniferatoxin on the isolated iris sphincter muscle of the rabbit was compared with the effects of capsaicin and bradykinin. The three compounds all contracted the sphincter muscle in a concentration-dependent manner. The contractions were inhibited by spantide II, a tachykinin antagonist. The concentration-response curve of resiniferatoxin was biphasic, yielding two EC50 values, one about 10,000 times lower than the other, the latter value being similar to that for capsaicin. The responses to resiniferatoxin, capsaicin or bradykinin were progressively reduced upon repeated application. The contraction evoked by either of the three compounds was not affected by thiorphan (an enkephalinase inhibitor) or captopril (an angiotensin-converting enzyme inhibitor). Pretreatment with capsaicin concentration dependently reduced the contractile response to a subsequent application of resiniferatoxin and vice versa. Bradykinin pretreatment reduced the resiniferatoxin response by about 50%; resiniferatoxin pretreatment completely abolished the response to bradykinin. Also, the contractile response to electrical stimulation was reduced concentration dependently by resiniferatoxin, capsaicin and bradykinin pretreatment. The response to electrical stimulation could be completely abolished by pretreatment with large doses of resiniferatoxin or capsaicin; pretreatment with large doses of bradykinin reduced the response by about 50%. Pretreatment with high concentrations of resiniferatoxin, or capsaicin, but not bradykinin, reduced the contractile response to the NK1 receptor agonist, [Sar9, Met(O2)11]SP (10(-8) M). The results suggest that the three compounds produce tachyphylaxis, mainly through partial (bradykinin) or complete (capsaicin, resiniferatoxin) exhaustion of the neuronal pool of releasable tachykinins although desensitization of tachykinin receptors may also contribute.

Animals↗